Significance Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Objectives Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human pediatric HIV infection to investigate whether short-term 9-[2-(phosphonomethoxy)-propyl]adenine (PMPA) administration can protect against perinatal infection. We previously demonstrated that 2 doses of PMPA (one dose given 4 hours before virus inoculation, and the 2nd dose 24 later) was effective in preventing infection. We now determine whether a single post-exposure dose of PMPA can still be effective. Results One newborn macaque was inoculated with SIVmac251 orally and given a single dose of PMPA 1 hour later. While untreated control infants from other study projects became persistently infected, the newborn macaque which received one dose of PMPA was persistenly virus-negative by PCR and virus culture, but made a transient antiviral IgG response. The animal is currently seronegative and healthy at 5 months of age. Future Directions Additional animals need to be added to this study to determine statistical significance. In addition, because current human trials with PMPA are currently using a lower dosage of PMPA, it is important to test the prophylactic efficacy of a lower PMPA dose in newborn macaques. KEYWORDS PMPA, vertical transmission, primate, prophylaxis, prevention, pediatrics